Case-Based Discussion on Management of Select Adverse Events | Part 4: General Audience Q&A

Please click to see the full Prescribing Information, including Boxed Warning, and see Important Safety Information below.

Watch the Q&A session.

This content is educational in nature and does not constitute medical advice. It should also not substitute for clinical decision making. 

This is part 4 of 4:

• Part 1: Overview of a Treatment Option for mTNBC
• Part 2: Case Presentation #1 and Q&A
• Part 3: Case Presentation #2 and Q&A
• Part 4: General Audience Q&A

INDICATIONS

TRODELVY® (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
• Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

IMPORTANT SAFETY INFORMATION
BOXED WARNING: NEUTROPENIA AND DIARRHEA

• Severe or life-threatening neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm³ or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
• Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤Grade 1 and reduce subsequent doses. 

CONTRAINDICATIONS

• Severe hypersensitivity reaction to TRODELVY.

WARNINGS AND PRECAUTIONS
Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Withhold TRODELVY for absolute neutrophil count below 1500/mm³ on Day 1 of any cycle or neutrophil count below 1000/mm³ on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 64% of all patients treated with TRODELVY and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK₁ receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. 

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia was 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function. 

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. 

ADVERSE REACTIONS

In the pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%). 

In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes.

DRUG INTERACTIONS
UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY. 

UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY.

Please click to see full Prescribing Information, including BOXED WARNING.

Video transcript:

Part 1: Overview of a Treatment Option for Metastatic Triple-Negative Breast Cancer

Dr Maria Theodoulou: Today we're going to be discussing a case-based discussion on management of select adverse events as it relates to TRODELVY (sacituzumab govitecan). This is a promotional program. It's sponsored by and provided on behalf of Gilead Sciences, and I'm being paid to give this presentation. The content in this program has been developed in accordance with FDA guidelines and is consistent with TRODELVY prescribing information. 

The objectives today are to understand TRODELVY key efficacy and safety data in second-line and later metastatic triple-negative breast cancer. The other objective is to discuss potential management strategies for certain adverse events that may be experienced with TRODELVY through hypothetical patient cases, and that's always fun because it brings it round into the clinic and it gives us a very, very clear perspective. 

The indications for TRODELVY and important safety information is that it is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease. It's also indicated for unresectable locally advanced or metastatic hormone receptor (HR)-positive patients who are HER2/neu negative. That includes IHC 0 by immunohistochemical assessment 1+ as well as 2+/ISH- for breast cancer patients who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. 

Important safety information is severe or life-threatening neutropenia, which can occur. Withhold TRODELVY for absolute neutrophil counts below 1500 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay. Severe diarrhea can also occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to at least a Grade 1 or better and reduce subsequent doses. Severe hypersensitivity reactions to TRODELVY have been documented, and that could be a contraindication. 

Dr Maria Theodoulou: TRODELVY is recommended as a Category 1, preferred treatment option for adult patients with recurrent unresectable or metastatic hormone receptor-positive HER2/neu negative breast cancer who have received prior treatment including endocrine therapy, a CDK4/6 inhibitor, and at least 2 lines of chemotherapy including at taxane, at least 1 of which was in the metastatic setting. It may be considered for a later line if not used as second-line therapy. TRODELVY is also recommended as a Category 1, preferred treatment option for adult patients with metastatic triple-negative breast cancer who received at least 2 prior therapies with at least 1 line for metastatic disease. It may be considered for later line if not used as second-line therapy. 

The ASCENT trial was a randomized, phase 3, open-label trial comparing TRODELVY to single-agent chemotherapy of physician's choice in patients with relapsed or refractory metastatic triple-negative breast cancer who had received 2 or more prior standard chemotherapies, at least 1 of them for metastatic disease. A subset of patients enrolled in ASCENT had received only 1 prior therapy in the metastatic setting and were eligible for enrollment if they had experienced disease relapse within 12 months of completion of either neoadjuvant or adjuvant therapy. ASCENT enrolled 529 patients at 88 sites in 7 countries between November 2017 and September 2019, and it was halted early in March 2020 due to evidence of efficacy per unanimous Data and Safety Monitoring Committee recommendations. Patients were randomized 1:1 to receive either TRODELVY 10 mg/kg as an IV infusion on Days 1 and 8 of a 21-day cycle or the physician's choice of single-agent chemotherapy, which included either eribulin, vinorelbine, gemcitabine, or capecitabine. Patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in patients without brain metastases as evaluated by an independent, centralized, and blinded group of radiology experts who assessed tumor response using RECIST criteria. There was a predefined maximum 15% cap for patients with brain metastases. Patients with known Gilbert’s disease or bone-only disease were excluded. 

Dr Maria Theodoulou: Key points here when we look at the demographics are that the patients were an overall age group with a median of about 54 years of age. The patient characteristics and demographics were well-balanced between the TRODELVY group and the single-agent chemotherapy group. Forty-two percent of the patients in the study group and 43% of the patients in the control group had liver metastases. Patients had received a median of 3 previous anti-cancer regimens, and there was no upper limit in the number of prior therapies. All patients had received previous treatment with taxanes, and 7% of patients in the TRODELVY group and 8% in the single-agent chemotherapy group had received prior treatment with a PARP inhibitor, and that is consistent and goes in line with the percentage of enrolled patients bearing germline BRCA1 and BRCA2 mutations. All of the patients had an ECOG performance status of 0 or 1. 

TRODELVY treatment resulted in significant median progression-free survival and median overall survival improvement over single-agent chemotherapy in the brain metastases-negative population. The primary endpoint of progression-free survival as determined by a blinded independent central review analysis per RECIST criteria in the brain met-negative group was met. The progression-free survival was 5.6 months with TRODELVY and 1.7 months with single-agent chemotherapy. The median overall survival on the right side of this slide in the brain metastases-negative group population was 12.1 months with TRODELVY and 6.7 months with single-agent chemotherapy. 

Dr Maria Theodoulou: Serious adverse reactions occurred in 27% of patients receiving TRODELVY. Serious adverse reactions in >1% of patients receiving TRODELVY included neutropenia (7%), diarrhea (4%), pneumonia (3%). Fatal adverse reactions have occurred in 1.2% of patients who received TRODELVY including respiratory failure and pneumonia. TRODELVY was permanently discontinued for adverse reactions in 5% of patients. Adverse reactions leading to permanent discontinuation in 1% or greater of patients who received TRODELVY were pneumonia and fatigue. Adverse reactions leading to a treatment interruption of TRODELVY occurred in 63% of patients. The most frequent (5% or greater) adverse reactions leading to a treatment interruption were neutropenia (47%), diarrhea (5%), respiratory infection (5%), and leukopenia (5%). Reactions leading to a dose reduction with the study drug occurred in 22% of patients. The most frequent (>4%) adverse reactions leading to a dose reduction were neutropenia (11%) and diarrhea (5%). G-CSF was used in 44% of patients who received TRODELVY. 

The most common adverse reaction occurring in 25% or more of patients treated with TRODELVY were fatigue (65%), diarrhea (59%), nausea (57%), alopecia (47%), constipation (37%), vomiting (33%), abdominal pain (30%), and decreased appetite (28%). The most common lab abnormalities occurring in 25% or more of patients treated with TRODELVY were decreased hemoglobin (94%), decreased lymphocyte counts (88%), decreased leukocyte count (86%), neutrophil count decreases (78%), increased glucose (49%), decreased calcium (36%), decreased magnesium (33%), decreased potassium (33%), increased albumin (32%), increased aspartate aminotransferase as well as alanine aminotransferase (the transaminases were about 26-27%), alkaline phosphatase increases (26%), and decreases in phosphate (26%). And certainly Table 3 of the PI explores this in much more detail. 

In the next few slides, we will review the warnings and precautions for TRODELVY, including adverse events that may be experienced and the recommended management strategies. 

Dr Maria Theodoulou: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3 to 4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6% of patients, and neutropenic colitis occurred in 1.4%. You need to withhold the TRODELVY for absolute neutrophil counts below 1500 on Day 1 of any cycle or a neutrophil count below 1000 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever, and administer G-CSF as clinically indicated or indicated in Table 1 of the US prescribing information. 

It is important to develop a proactive plan for neutropenia management; as you start a patient on TRODELVY, ensure that you take appropriate steps so that you can help manage with G-CSF if needed. When starting a patient on TRODELVY, consider which G-CSF products are covered by the patient's insurance plan. Will prior authorization be required? When is it prudent to have G-CSF products on hand? And for G-CSF use with the treatment of TRODELVY, what are factors to consider? 

If patients experience severe neutropenia, dose modifications for TRODELVY may be recommended. Withhold or discontinue TRODELVY to manage adverse reactions as described here. Do not re-escalate the dose after a dose reduction for adverse reaction, ever. Reduce TRODELVY dose by 25% from the original dose and administer G-CSF at the first occurrence of Grade 4 neutropenia lasting 7 days or longer, that's a neutropenia of 500 or less, or Grade 3 to Grade 4 with a febrile neutropenia, or at time of scheduled treatment, Grade 3 to 4 neutropenia, which delays dosing by 2 or 3 weeks for recovery to Grade 1 or lower. So again, the dose reduction is for Grade 4 neutropenia lasting 7 days or longer, Grade 3 to 4 febrile neutropenia, or at the time of scheduled treatment, Grade 3 to 4 neutropenia, which delays dosing by 2 or 3 weeks for recovery to Grade 1 or lower. If there is a second occurrence, reduce TRODELVY dose by 50% from the original dose and administer G-CSF. If there is a third occurrence, then you have to discontinue TRODELVY and certainly support the patient with G-CSF. If at time of scheduled treatment, if there is a Grade 3 to 4 neutropenia, which delays dosing beyond 3 weeks for recovery to Grade 1 or lower, then discontinue TRODELVY and administer G-CSF. If the patient develops an infusion-related reaction, slow or interrupt the infusion rate. Permanently discontinue TRODELVY for life-threatening infusion-related reactions. 

Dr Maria Theodoulou: TRODELVY can cause GI side effects. It can cause diarrhea. Diarrhea occurred in 64% of patients treated with TRODELVY. Grade 3 to 4 diarrhea occurred in 11% of patients. One patient had an intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in less than 1% of patients (0.7%). Withhold the TRODELVY for Grade 3 to 4 diarrhea and resume when a patient is Grade 1 or normal. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially as a loading dose followed by 2 mg with every episode of diarrhea for a maximum of 16 mg for the day. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures, whether fluid and electrolyte support, may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication for subsequent treatments (ie, atropine). 

Be sure to advise patients of the risk of diarrhea. Education, education, education. Instruct your patients to contact their healthcare provider immediately if they experience any of the following symptoms: Diarrhea for the first time, black or bloody stools, symptoms of dehydration such as lightheadedness, dizziness, or faintness, inability to take fluids by mouth due to nausea or vomiting, inability to control diarrhea within 24 hours. 

Dr Maria Theodoulou: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY. Severe signs and symptoms include cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3 to 4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after the completion of each infusion. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions. 

Nausea occurred in 64% of all patients treated with TRODELVY, and Grade 3 to 4 nausea occurred in 3% of patients. Vomiting occurred in 35% of patients, and Grade 3 to 4 vomiting occurred in 2% of these patients. Premedicate these patients with 2- or a 3-drug combination regimen, such as dexamethasone with either a 5-HT3 receptor antagonist or an NK₁ receptor antagonist, as well as other drugs as indicated for prevention of chemotherapy-induced nausea and vomiting. Withhold TRODELVY for doses for Grade 3 nausea or Grade 3 to 4 vomiting and resume with additional supportive measures when they have resolved to at least Grade 1 or less. Additional antiemetics and other supportive measures may also be employed as clinically indicated. Patients should all be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. 

Dr Maria Theodoulou: Additional dose modification for TRODELVY may be recommended for severe non-neutropenic toxicities. Withhold or discontinue TRODELVY to manage adverse reactions as described here. Do not re-escalate the dose after a dose reduction for adverse reactions. Reduce the TRODELVY dose by 25% from the original dose at the first occurrence of the following non-neutropenic events: a Grade 4 non-hematologic toxicity of any duration or any Grade 3 to 4 nausea, vomiting, or diarrhea due to treatment that is not controlled with antiemetics and antidiarrheal agents, or other Grade 3 to 4 non-hematologic toxicities persisting more than 48 hours despite optimal medical management. At the time of the scheduled treatment, Grade 3 to 4 non-neutropenic hematologic or non-hematologic toxicity, which delays the dose by 2 or 3 weeks for recovery to Grade 1 or lower. If there's a second occurrence, reduce the TRODELVY dose by 50% from the original dose. If there's a third recurrence, then no more TRODELVY, TRODELVY is now discontinued. In the event of Grade 3 to 4 non-neutropenic hematologic or non-hematologic toxicity, which does not recover to Grade 1 or lower within 3 weeks, discontinue TRODELVY. If the patient develops an infusion-related reaction, as we said earlier, slow or interrupt the infusion rate, and permanently discontinue TRODELVY for life-threatening infusion-related reactions. 

Patients homozygous for UGT1A1 in the 28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3 to 4 neutropenia was 58% in patients homozygous for this enzyme and 49% in patients heterozygous for the UGT1A1 on 28 allele, 43% in patients homozygous for the wild-type allele. The incidence of Grade 3 to 4 anemia was 21% in patients homozygous for this enzyme, 10% in patients heterozygous, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function. Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant patient. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. We have to advise patients who are pregnant. We have to advise these women of these potential risks to a fetus, discuss contraception, and make sure that we've educated our patients. If a patient is going to become pregnant after using TRODELVY, she has to wait at least 6 months after the last dose. If it's a male who is receiving TRODELVY, they need to wait at least 3 months after the last dose. We need to discuss this. We need to educate our patients and make sure that they're using appropriate contraception.

Dr Maria Theodoulou: In the pooled safety population, again, this was in 4 different studies using TRODELVY, the most common adverse reactions including laboratory abnormalities that were seen in 25% or greater patients were decreased leukocyte count, decreased neutrophil count, hemoglobin, diarrhea, nausea, lymphocyte count, fatigue, alopecia at 45%, constipation at 37%, increased glucose (37%), decreased albumin (35%), as well as looking at transaminases, decreased creatinine clearance, decreased potassium and sodium in 28% of patients. Specifically in the ASCENT study, in those patients with locally advanced or metastatic triple-negative breast cancer, the most common adverse reactions were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. These were seen in 25% or greater. When we're looking at the frequent serious adverse reactions (SAR) like neutropenia (7%), diarrhea (4%), pneumonia (3%), SAR were reported in 27% of patients. The most common Grade 3 to 4 lab abnormality in the ASCENT study was reduced neutrophils, leukocytes, and lymphocytes. If we look at the TROPiCS-02 study, for locally advanced or metastatic hormone receptor-positive patients that are HER2/neu negative, again, in those patients, the most common Grade 3 to 4 laboratory abnormalities were reduced neutrophils and leukocytes seen in about 25% or more of patients. 

Drug-drug interactions, important. We need to know what our patients are taking. UGT1A1 inhibitors: Concomitant administration of TRODELVY with these inhibitors can increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering these UGT1A1 inhibitors with TRODELVY, and an example of this is milk thistle. And often our patients go to holistic stores, they take what they think are complementary medications. We have to be aware of them. So a good medics, a good interview, and allowing the patient to avoid any potential adverse reaction from a drug-drug interaction. If you have an enzyme inducer, a UGT1A1 inducer, exposure to the component of SN-38 can reduce the effectivity in patients who are receiving these inducers. Avoid administering UGT1A1 inducers with TRODELVY, and examples of those are phenobarbital or the HIV drug rifampicin.

Part 2: Case Presentation #1 and Q&A

Dr Maria Theodoulou: So now we're going to move forward with a hypothetical patient case. This becomes the fun part of the program, which is included, and these cases have been adapted from cases provided by clinicians. They are only for illustrative purposes. The information in this program does not constitute the provision of medical advice and should not substitute for clinical decision-making, and images do not depict real patients. 

So we're going to talk right now about Agnes, who's 36 years old. Agnes found a lump in her right breast on self-examination. She was diagnosed with a clinical Stage 1. She underwent a lumpectomy with sentinel lymph node biopsy. She receives radiation therapy. She was found to have a T1, N1mic, triple-negative breast cancer, ER negative, PR negative, HER2/neu IHC 2+/ISH-. So she's HER2 low. She is treated with adjuvant AC followed by T. Six months after her adjuvant treatment, She develops bloating and loss of appetite. 

Dr Maria Theodoulou: A CAT scan is performed and it reveals metastatic lesions in the liver. A biopsy of the liver lesion is performed. Pathology reports again ER negative, PR negative, HER2/neu IHC 2+/ISH- metastatic breast cancer. Now she's PD-L1 positive and she has been assessed for the germline BRCA gene and she has a wild type. She begins immunotherapy with pembrolizumab and paclitaxel. Ten months after first-line treatment for her metastatic triple-negative breast cancer, she develops a persistent cough. CT followed by biopsy reveals new metastatic lesion in the lung and now she's symptomatic, and she begins treatment with TRODELVY. 

So now we're going to move forward to some of the audience questions and your participation. What potential adverse reactions may require premedication when using TRODELVY? And you can select any and all that may apply. A. Edema; B. Infusion reactions; C. Chemotherapy-induced nausea and vomiting; D. Diarrhea. 

Dr Maria Theodoulou: The correct answers are: Infusion reactions, Chemotherapy-induced nausea and vomiting, and Diarrhea. Premedication for prevention of infusion reactions and prevention of chemotherapy-induced nausea and vomiting is recommended. Those patients who exhibit an excessive cholinergic response to treatment with TRODELVY, for instance abdominal cramping, diarrhea, salivation, can receive appropriate premedication like atropine for subsequent treatments. 

So the correct answers were infusion reactions, chemotherapy-induced nausea and vomiting, and diarrhea. 

Dr Maria Theodoulou: Agnes completes Cycle 1 of TRODELVY (Day 1 and Day 8 infusions), and now she comes in for Cycle number 2. And on Day 1, Agnes has labs taken, and we all know that we need to check those labs before we move forward with the next infusion. And now her ANC is 900. She has a Grade 3 neutropenia. 

How could Agnes’s Grade 3 neutropenia be managed? Select any and all of the following 5 answers that apply. A. Administer G-CSF; B. Continue TRODELVY dose and schedule as is; C. Withhold TRODELVY on Cycle 2, Day 1; D. Reduce TRODELVY dose by 25%; E. Discontinue TRODELVY. 
So how could Agnes’s Grade 3 neutropenia be managed? Select all that may apply. 

Dr Maria Theodoulou: The correct answers are: Administer G-CSF, Withhold TRODELVY on Cycle 2, Day 1. At this point the TRODELVY dose does not need to be reduced or discontinued. Recall that TRODELVY should be withheld if a patient has an ANC below 1500 on Day 1 of any cycle or neutrophil count below 1000 on Day 8 of any cycle, and administer G-CSF as indicated.

Agnes's care team withheld the TRODELVY and administered short-acting G-CSF daily for 5 days. Labs were taken 1 week after the Grade 3 neutropenia event, revealed recovery to Grade 1. 

So after a 1-week delay, for Cycle 2, Day 1, what steps could be taken with Agnes’s treatment with TRODELVY (select all that may apply)? A. Utilize G-CSF as secondary prophylaxis; B. Continue TRODELVY dose as is; C. Reduce TRODELVY dose by 25%; D. Reduce TRODELVY dose by 50%; E. Discontinue TRODELVY. 

Dr Maria Theodoulou: So this patient received 5 consecutive days of G-CSF, and 1 week after her Grade 3 neutropenia, she recovers to Grade 1. The correct answers are A and B: Utilize G-CSF as secondary prophylaxis, Continue TRODELVY dose as is. 

In Agnes's case, the Grade 3 neutropenia recovered to Grade 1 within 1 week. Therefore, dose reduction was not needed. Recall from the TRODELVY dose modification table for severe neutropenia that you reduce TRODELVY dose by 25% from the original dose and administer G-CSF at the first occurrence of Grade 4 neutropenia lasting 7 days or longer, or Grade 3 to 4 febrile neutropenia, or at the time of scheduled treatment, Grade 3 to 4 neutropenia, which delays dosing by 2 or 3 weeks for recovery to Grade 1 or lower. Agnes recovered within 7 days. If there is a second occurrence, reduce the TRODELVY dose by 50% from the original dose and administer G-CSF. If there's a third recurrence, then you no longer move forward with TRODELVY and administer G-CSF. If at the time of scheduled treatment, a Grade 3 to 4 neutropenia delays dosing beyond 3 weeks for recovery to Grade 1 or lower, then discontinue TRODELVY and administer G-CSF. 

Dr Maria Theodoulou: Agnes's care team continues TRODELVY dose and schedule as is. G-CSF was ordered as secondary prophylaxis for her subsequent infusions. 

What G-CSF regimen may be considered for secondary prophylaxis (select all that may apply)? A. Administer long-acting G-CSF subcutaneously on Day 1; B. Administer short-acting G-CSF subcutaneously on Day 3 and 4; C. Administer long-acting G-CSF subcutaneously on Day 9. 

Dr Maria Theodoulou: And the correct answer here is B and C. You don't want to administer long-acting G-CSF on Day 1. You'll not be able to get your dose in appropriately on Day 8. So you use short-acting G-CSF on Days 3 and 4, and on Day 9 when you're going to have a 2-week interval on this 21-day cycle, then you can use long-acting G-CSF. 

This patient continues on TRODELVY, and now she experiences fatigue that was limiting her daily activities and was not relieved by rest.  

Dr Maria Theodoulou: To assist your patient with management of fatigue, what might you recommend? A. Planning time to relax and rest and creating a schedule that works for them; B. Trying to get 7 to 8 hours of sleep each night; C. Trying to stay active but discussing with you before starting a new exercise routine; D. Drinking plenty of water and eating well; E. Reducing stress by trying meditation, yoga, reading, or keeping a diary.
 
Dr Maria Theodoulou: According to the NCI Chemotherapy and You: Support for People with Cancer that was published in September 2018, every one of these – A, B, C, D, or E – would be appropriate.

Part 3: Case Presentation #2 and Q&A

Dr Maria Theodoulou: We have another case. This is Marion. She's 55 years old. She presents with pain and tenderness in her left breast area. She's diagnosed with a clinical stage II with a T2, N1 triple-negative breast cancer. She's ER/PR negative. HER2 is IHC 1+. She receives neoadjuvant pembro plus carboplatinum and paclitaxel followed by pembro with AC. She undergoes bilateral mastectomy with sentinel lymph node biopsy and dissection followed by radiation therapy. She continues on adjuvant pembrolizumab. She does well for 3 years after adjuvant treatment. 

She starts to develop persistent coughing. A CAT scan followed by a biopsy reveals metastatic lesions in the lung, with similar pathology to her original breast cancer diagnosis. She's germline BRCA wild type. She's PD-L1 negative. So she's started on carboplatinum plus gemcitabine. Twelve months after first-line metastatic triple-negative breast cancer treatment, she starts to complain of abdominal discomfort. A CT followed by a biopsy reveals new metastatic disease in her liver. Marion begins treatment with TRODELVY. 

Dr Maria Theodoulou: She completes Cycle 1 of TRODELVY (Day 1 and Day 8 infusions). Now remember this is a Day 1, Day 8 of a 21-day cycle. On Day 12, she experienced 4 episodes of diarrhea within 24 hours. This is a Grade 2 diarrhea. 

How could Marion's Grade 2 diarrhea be managed (select all that may apply)? A. Evaluate for infectious causes. After infectious cause is ruled out, you initiate loperamide 4 mg initially followed by 2 mg for each episode to no more than 16 mg per day; B. Additional supportive measures (ie, fluid and electrolyte substitution) as clinically indicated; C. Reduce TRODELVY dose by 25%; D. Discontinue TRODELVY. 

Dr Maria Theodoulou: So A and B are the correct answers here. Since the patient experienced Grade 2 diarrhea, TRODELVY does not need to be withheld, dose reduced, or discontinued at this time. If this were a Grade 3 or Grade 4 diarrhea, then you would withhold TRODELVY and resume when resolves to a Grade 1 or lower. 

Recall that at the onset of diarrhea, you evaluate for infectious causes and if negative, you promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily, and then you discontinue the loperamide 12 hours after the diarrhea resolves. 

Dr Maria Theodoulou: Marion started loperamide 4 mg initially followed by 2 mg for each episode as instructed by her treatment team to no more than 16 mg for the day. After 3 days, Marion's diarrhea resolved. She discontinued loperamide 12 hours later. 

For Cycle 2, Day 1, what steps could be taken with Marion's treatment with TRODELVY? Do we continue TRODELVY as is? Do we withhold TRODELVY on Day 1, Cycle 2? Do we reduce TRODELVY dose by 25%, or indeed reduce it by 50%? Or do we discontinue TRODELVY? 

Dr Maria Theodoulou: We continue TRODELVY as is. Remember that she resolved within 3 days with loperamide use. There's no reason in this case to withhold, reduce, or discontinue TRODELVY. 

In Marion's case, she experienced a Grade 2 diarrhea. Recall from the TRODELVY dose modification table for severe non-neutropenic toxicity that the TRODELVY dose is reduced by 25% from the original dose at the first occurrence of either Grade 4 non-hematologic toxicity of any duration, Grade 3 or 4 nausea, vomiting, or diarrhea due to treatment that is not controlled with antiemetics and antidiarrheal agents, other Grade 3 or 4 non-hematologic toxicity persisting more than 48 hours despite optimal medical management, or at the time of scheduled treatment, Grade 3 to 4 non-neutropenic hematologic or non-hematologic toxicity, which delays the dose by 2 to 3 weeks for recovery to Grade 1 or lower. If there's a second recurrence, TRODELVY dose is then reduced by 50%. Patients are off TRODELVY if a third dose reduction is needed. And in the event of Grade 3 to 4 non-neutropenic hematologic or non-hematologic toxicity, which does not recover to Grade 1 or lower within 3 weeks, discontinue TRODELVY. 

Dr Maria Theodoulou: Marion completed Cycle 2 of TRODELVY, both Day 1 and Day 8 infusions, of that 21-day cycle and Cycle 3 Day 1. Now she comes in for Cycle 3, Day 8, and her labs reveal an ANC of 450. This is a Grade 4. 

How could Marion's Grade 4 neutropenia be managed? You can select 1 or as many or all. A. Administer G-CSF; B. Continue TRODELVY dose and schedule as is; Withhold TRODELVY on Cycle 3, Day 8; Reduce TRODELVY dose by 25%; Discontinue TRODELVY. 

Dr Maria Theodoulou: At this point, we do not know how long her neutropenia lasted and therefore we do not need to dose reduce or discontinue TRODELVY. All we had to do was withhold it. Administer the G-CSF. 

Again, remember that TRODELVY should be withheld if a patient has an ANC below 1500 on Day 1 or any cycle or a neutrophil count below 1000 on Day 8 of any cycle, and you should be administering G-CSF as clinically indicated. 

Dr Maria Theodoulou: Marion's Grade 4 neutropenia persisted for 8 days before recovering. For Cycle 4, Day 1, What steps could be taken with Marion's treatment with TRODELVY (select all that may apply)? A. Utilize G-CSF as secondary prophylaxis; B. Continue TRODELVY dose as is; C. Withhold TRODELVY on Cycle 4, Day 1; D. Reduce TRODELVY dose by 25%; E. Reduce TRODELVY dose by 50%; F. Discontinue TRODELVY. 

Dr Maria Theodoulou: Now remember, in Marion's case, Grade 4 neutropenia lasted for more than 7 days. So the correct answer is to utilize G-CSF as secondary prophylaxis, and because her neutropenia lasted for more than 7 days, a dose reduction for TRODELVY should be considered, reducing it by 25%. 

So again, recalling from the TRODELVY dose modification table for severe neutropenia, reduce TRODELVY dose by 25% from the original dose and administer G-CSF at the first occurrence if a patient has Grade 4 neutropenia lasting 7 days or longer, if they have Grade 3 or 4 febrile neutropenia, or at the time of scheduled treatment, Grade 3 to 4 neutropenia, which delays dosing by 2 or 3 weeks for recovery to Grade 1 or lower. If there's a second occurrence, obviously you reduce the TRODELVY dose by 50% from the original dose and administer G-CSF. If there is a third occurrence, then discontinue TRODELVY and administer G-CSF. If at a time of a scheduled treatment there is a Grade 3 to 4 neutropenia, which delays dosing beyond 3 weeks for recovery to Grade 1 or lower, then discontinue TRODELVY and administer G-CSF.

Part 4: General Audience Q&A

Moderator: Alright, we have a few questions here. The first one is: How are you counseling patients about alopecia? 

Dr Maria Theodoulou: Okay, great question. There was alopecia seen, and we need to talk about the potential for hair thinning and, in those few patients that might have complete hair loss, remember alopecia is Grade 1, Grade 2. So I talk to them about it, I warn them about it. I tell them that it may not happen but to be prepared for it. And I think if a patient is prepared for it, knowing that she has disease progression and she's trying to do everything she can to prolong progression - time to progression, as well as her overall survival, that becomes a more palatable side effect if the patient is aware of it. So I do tell them that it's a possibility. It may not happen in everyone. 

Moderator: All right, thank you. The next question is: Some patients are hesitant to take loperamide because of constipation. What has worked with you in the past to help patients start loperamide if needed? 

Dr Maria Theodoulou: Well, I think looking at some of the data that we have and knowing that once a patient resolves their diarrhea, they shouldn't be taking loperamide after 12 hours. You know, we're really big on hydrating our patients, and oftentimes we know that patients who are receiving therapeutic regimens for their disease can be fatigued, can be tired. Often they're not hydrating well, they're worried about nausea even when you counsel them to do so. In order to exact that, we can bring them in for IV fluid resuscitation the day after to make them feel better. But oftentimes it's really going over loperamide, the mechanism of action, how it works, and when to stop it. And having a phone number and recalling those patients the day after their treatment as well as speaking to them a day after they start having diarrhea to be able to counsel them as to when to stop the loperamide. That is often reassuring for patients. 

Moderator: Thank you. Another question is, and this goes to some of the patient examples that we talked about: In what patients do you consider long-acting or short-acting G-CSF? 

Dr Maria Theodoulou: Alright, so remember that short-acting G-CSF is a growth factor that works quickly and has a very short half-life. The rationale for long-acting growth factors, long-acting G-CSF, is for those patients that are on dose-dense regimens or regimens that are going to be administered again after 14 days. We do not administer any growth factors within 14 days after a patient receives long-acting G-CSF or giving them chemotherapy prior to that. So for Day 1, Cycle Day 1, where there's only a 7-day interval, I would use the short-acting G-CSF and on Day 8, because I have 14 days before my next infusion, I would consider the longer-acting G-CSF that's given in only 1 subcutaneous injection the day after that chemotherapy regimen.

US-TROP-1229 02/2024

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